Project Summary Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects millions of people worldwide. Disease progression includes inflammation of the synovium, a membrane that encapsulates the joint and contains the synovial fluid. The synovium, composed mostly of fibroblasts, is central to disease pathogenesis in RA. It forms an invasive tissue called pannus that recruits immune cells such as T cells and B cells, destroys articular cartilage in the joint, and mediates signaling leading to activation of bone-resorbing osteoclasts. In this project, we will study synovial fibroblasts obtained from fresh tissue discarded during joint replacement surgery. Our work will define the cellular population structure of fibroblasts in the synovium by assaying single-cell gene expression profiles. In RA, the synovium has a heterogeneous mixture of signaling molecules and cell types that influence a positive feedback loop between the tissue and the cells of the immune system. This project aims to define a detailed transcriptional network synergistically activated by tumor necrosis factor (TNF) and interleukin 17 (IL17A). This work will establish basic knowledge about the transcriptional functions of synovial fibroblasts, so it may have broad implications for RA and other diseases that are mediated by fibroblasts in connective tissues such as psoriasis and interstitial pneumonia.